Cure for MS stopping the immune response

C
Bone marrow transplantations seems to get rid of autoimmune cells in MSers. #MSBlog #MSResearch

“This is a study for immunology geeks. In short MSers who have autologous bone marrow transplantation (BMT), i.e. their immune systems are rebooted using their own stem cells, have evidence to support that the type of immune cells that come back after the transplant are not autoreactive  These results support the concept of rebooting the immune system to treat autoimmunity. Interestingly, in MSers on natalizumab these cells are still present and are prevented to get into the brain and spinal. This is why MS comes back with a vengeance when natalizumab is stopped. Natalizumab is like sticky plaster or band aid; remove the sticky plaster and the disease is back. BMT and other induction or rebooting therapies get to the core of  the problem; i.e. they attempt to cure autoimmunity. You have to realise, however, that BMT will not be effective in all people treated. When the immune system is ablated some autoreactive cells may survive and come back when the immune system reconstitutes itself. “

“Would you have a bone marrow transplant (BMT)? The risks associated with it are very high; it has a mortality (chance of dying from the procedure) approaching 5%. Although in the best BMT units this figure is below 1%. I personally think treatment with alemtuzumab is preferable; it probably achieves a similar result with less risk of death. Alemtuzumab, however, does have its own risks of other types of autoimmunity developing when the immune system recovers.”

Epub: Burman et al. T cell responses after hematopoietic stem cell transplantation for aggressive relapsing-remittingmultiple sclerosis. Immunology. 2013 May 30.

Background: Autologous hematopoietic stem cell transplantation (HSCT) for relapsing-remitting multiple sclerosis is a potentially curative treatment, which can give rise to long-term disease remission. However, the mode of action is not yet fully understood. 


Objective: The aim of the study was to evaluate similarities and differences of the CD4+ T cell populations between HSCT-treated MSers (n=12) and healthy controls (n=9). 

Methods: The investigators’ performed phenotyping of memory T cells, Tregs, T helper type 1 (Th1) and T helper type 17 (Th17) cells. Further, T cell reactivity to a tentative antigen: myelin oligodendrocyte glycoprotein was investigated in these MSer populations. MSers treated with natalizumab (n=15) were included as a comparative group. White blood cells were analyzed with flow cytometry and T cell culture supernatants were analyzed with magnetic bead panel immunoassays. 

Results: HSCT-treated MSers had similar levels of Tregs, Th1 and Th17 cells as healthy subjects, whereas natalizumab-treated MSers had lower frequencies of Tregs, and higher frequencies of Th1 and Th17 cells. Cells from HSCT-treated MSers cultured with overlapping peptides from myelin oligodendrocyte glycoprotein produced more TGF-β1 than natalizumab-treated MSers suggestive of a suppressive response. Conversely, T cells from natalizumab-treated MSers cultured with those peptides produced more IL-17, IL-1 and IL-10 indicating a Th17 response. 

Conclusion: In conclusion, they demonstrate circumstantial evidence for the removal of auto-reactive T cell clones as well as development of tolerance after HSCT. These results parallel the long-term disease remission seen post HSCT.

“The following picture explains the steps involved in performing an autologous BMT. After step 4 the immune system is very suppressed and the person needs bone marrow support; transfusions for anaemia and low platelets for bleeding and antibiotics to prevent or treat infections. The infections can be very serious and life threatening.” 



About the author

Prof G

Professor of Neurology, Barts & The London. MS & Preventive Neurology thinker, blogger, runner, vegetable gardener, husband, father, cook and wine & food lover.

19 comments

  • "Would you have a bone marrow transplant (BMT)?

    I'll answer this one on behalf the the venerable Mrs C

    YES IN A HEARTBEAT

    Regards as always

    • We can phrase it in another way:
      Say 19 close family members and your (siblings, children, nephews…) all have MS.
      Would you advise all 20 of you to do a HSCT?

    • If you are trying to imply that you will re-acquire MS after HSCT, I think this is most improbable. First, you would have to experience the same immune system chalenges (sequence and timing) that let to MS in the first place. Most of these chalenges happen during childhood and it is unlikeley you would experience them in the same sequence in adult hood.

      Secondly, genetics have a role in MS but it is only minor. For example, if you are an identicle twin and your sibling has MS, you only have a 30% chance of acquering MS (this is with the same DNA).

      So, it is probably unlikely that you would re-acquire MS after HSCT:

      http://europepmc.org/abstract/MED/19252771

    • Tony, I answered the question as proposed. If we really want to qualify the question to the study above then the question would be irrelevant as my Wife has ppms and as you can she she wouldn't meet the qualifying criteria.

      If you're asking me would she have BMT to put HER MS into long-term disease remission ('CURE') and could mean repeating the procedure ? then the answer would be yes again.

      I appreciate this treatment is no walk in the park, then again I'm sure you realise niether is MS. A risk of less than 1% in my opinion is worth taking. I have met a Lady who has had this treatment carried out here in the UK and at the time had no regrets despite being unfortunate to experience complications, as it appeared to have stopped her MS.

      btw still unsure where you're coming from with 20x

      Regards as always

    • I had this conversation with my neuro who looked at me in horror when I said I would risk the 5% mortality rate. I too would have it in a heartbeat.

    • You don't need to take a risk of a 5% mortality rate. Alemtuzumab appears to do the job just as well and is much safer.

  • Dr. Richard Burt at Northwestern University in Chicago is using a non-meyoblative protocol for a second line therapy in a phase III trial. This is a much less aggresive protocol than the meyoblative HSCT which has resulted in no deaths.

    I would definetely opt for this as a second line therapy of Tsybari or other drugs since this would halt disease progression in the right patient. Hopefully this will be approved in within the next 10 years.

    http://msj.sagepub.com/content/18/6/772.full.pdf+html

  • So we have two treatments (HSCT, Campath used for cancer) that work very well in MS patients and stops the disease to over 80% of patients, and we're not offering them to patients, or we're going to offer this treatment when they are really bad (2nd line, HSCT maybe 3rd line?). Why not offer to patient all options, consult with them and let them decide.

    • Because others who don't have the disease unfortunately think they know what's good for those with the disease.

      Neurologists also seem to have been extremely conservative in treatment, presumably in part because there wasn't any treatment and the disease can be hard to definitively diagnose early. We need to get this to change. If it wasn't for the cost of the drugs, I think we'd have an easier time fighting for change.

  • One thing that may be a concern is a chance of acquiring a secondary autoimmune disease which is estimated to be about 10%. The secondary autoimune disease is different from the primary autoimmune disease (MS), but it is thought that when the immune system is depleted, all of the regulatory mechanisms (Tregs) take a while to recover which may allow a window for secondary immunity to occur. I think this could be a problem even with the less toxic non-myeoblative protocols.

    http://www.ncbi.nlm.nih.gov/pubmed/21596847

    But if I was declining rappidly I would take the chance.

  • Prof G:

    How does this fit in with the viral theory about MS? It would seem this study, and other like it with HSCT, suggest that MS is purely driven by autoimmunity. Would this study argue against the viral theory?

    • Could be EBV antigens cross-reactive with myelin antigens are driving an autoimmune response (molecular mimicry). If you get rid of the autoreactive T cells then the problem goes away, though if the EBV is still around then there is the risk of activation of the grafted cells to retrigger autoimmunity as the graft is autologous. Only time would tell whether this is the case.
      http://www.ncbi.nlm.nih.gov/pubmed/21486137

    • Yes, they are. That does not mean that they will never disappear. It may take decades for long-lived plasma cells that make OCBs to perish. The same thing happens with Alemtuzumab.

      See: Hill-Cawthorne GA, Button T, Tuohy O, Jones JL, May K, Somerfield J, Green A, Giovannoni G, Compston DA, Fahey MT, Coles AJ. Long term lymphocyte reconstitution after alemtuzumab treatment of multiple sclerosis. J Neurol Neurosurg Psychiatry. 2012 Mar;83(3):298-304. or

      http://www.ncbi.nlm.nih.gov/pubmed/22056965

  • There is also evidence that it may not be a matter of a faulty immune system with autoreactive immune cells, which can be found in normal people as well. It could be a faulty regulatory system whose role is to maintain homeostatis in the immune system (there is indications that the regulatory system in MS is not effective). It seems HSCT may re-introduce self-tolerance:

    http://www.ncbi.nlm.nih.gov/pubmed/18256318

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